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Michele Fornaro,1 Domenico De Berardis,2 Ann Sarah Koshy,3 Giampaolo Perna,4 Alessandro Valchera,5 Davy Vancampfort,6 Brendon Stubbs7,8 1New York Psychiatric Institute, Columbia University, New York, NY, USA; 2National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, Teramo, Italy; 3St. John’s National Academy of Health Sciences, Bangalore, India; 4Department of Clinical Neurosciences, Hermanas Hospitalarias - Villa San Benedetto Menni Hospital, FoRiPsi, 5Hermanas Hospitalarias, FoRiPsi Villa S. Giuseppe Hospital, Ascoli Piceno, Italy; 6Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium; 7Physiotherapy Department, South London and Maudsley NHS Foundation Trust, 8Health Service and Population Research Department, Institute of Psychiatry, King’s College London, London, UK Background: Uncertainty exists regarding the prevalence and clinical features associated with the practice of polypharmacy in bipolar disorder (BD), warranting a systematic review on the matter.Methods: Three authors independently searched major electronic databases from inception till September 2015. Articles were included that reported either qualitative or quantitative data about the prevalence and clinical features associated with polypharmacy in adult cases of BD.Results: The operative definitions of polypharmacy adopted across varying studies varied, with concomitant use of two or more psychotropic medications or use of four or more psychotropic medications at once being the most common and the most reliable, respectively. Regardless of type or current mood episode polarity of BD, prevalence rates up to 85% and 36% were found using the most permissive (two or more medications at once) and the most conservative (four or more) operative definitions for polypharmacy, respectively. Point prevalence prescription rates of one or more antidepressant or antipsychotic as part of a polypharmacy regimen occurred in up to 45% or 80% of the cases, respectively, according to the most permissive definition of polypharmacy. In contrast, lithium prescription rates ranged from 13% to 33% in BD patients receiving polypharmacy according to conservative and permissive definitions, possibly suggesting a reduced need for augmentation of combination strategies for those cases of BD with a favorable lifetime lithium response and/or long-lasting treatment as well as less likelihood of lithium response over the time most severe cases possibly exposed to a more complex polypharmacy overall.Limitations: “Apples and oranges” bias; publication bias for most recently introduced compounds.Conclusion: Polypharmacy is common among people with BD across varying type and mood episode phases of illness. Special population, including BD patients at high risk of familial load for suicidal behavior, solicit further research as well as the plausible “protective” role of lithium toward polypharmacy in BD. The PROSPERO registration number is CRD42014015084. Keywords: bipolar disorder, polypharmacy, prevalence, systematic review&nbsp

Domenico De Berardis,1–3 Laura Orsolini,3–5 Nicola Serroni,1 Gabriella Girinelli,1–3 Felice Iasevoli,3–6 Carmine Tomasetti,3–6 Monica Mazza,3–7 Alessandro Valchera,3–8 Michele Fornaro,9 Giampaolo Perna,10–12 Monica Piersanti,13Marco Di Nicola,14 Marilde Cavuto,15 Giovanni Martinotti,2 Massimo Di Giannantonio21NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital "G Mazzini", Teramo, Italy; 2Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University G d'Annunzio, Chieti, Italy; 3Polyedra, Teramo, Italy; 4United Hospitals, Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy; 5School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Hertfordshire, UK; 6Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy; 7Department of Health Sciences, University of L'Aquila, L'Aquila, Italy; 8Villa S Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy; 9Department of Scienze della Formazione, University of Catania, Catania, Italy; 10Hermanas Hospitalarias, FoRiPsi, Department of Clinical Neurosciences, Villa San Benedetto Menni, Albese con Cassano, Como, Italy; 11Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, the Netherlands; 12Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA; 13Hospital Pharmacy, Hospital G Mazzini, ASL 4 Teramo, Italy; 14Institute of Psychiatry and Psychology, Catholic University of Sacred Heart, Rome, Italy; 15IASM, L'Aquila, ItalyAbstract: Melatonin (N-acetyl-5-methoxytryptamine) has been discovered as a hormone secreted by the pineal gland, even though it is also synthetized in various other organs, tissues, and cells. The circadian rhythm of melatonin is often used as an indicator phase position since it is a well-defined, high-amplitude rhythm controlled by the hypothalamic suprachiasmatic nuclei. Melatonin production is controlled by this endogenous circadian timing system. It peaks during the night and is suppressed by daylight. Mood spectrum disorders, including bipolar disorder (BD), major depressive disorder (MDD), and seasonal affective disorder (SAD), have been observed to be accompanied by circadian dysregulation as well as dysregulation in melatonin secretion. Simultaneously, it has also been documented that disruptions in circadian rhythms, including the sleep/wake cycle, though environmental means can produce mood-related problems in vulnerable individuals. These findings suggested that altered circadian rhythms might be biological markers of these disorders. As melatonin is considered a chronobiotic factor, ie, able to entrain the circadian rhythms of several biological functions (eg, activity/rest, sleep/wake, body temperature, endocrine rhythms, etc), its use may provide a new therapeutic approach for the treatment of affective disorders. However, the available evidence is controversial. This review summarizes the data published so far about reliable evidence on the role of melatonin in affective disorders.Keywords: melatonin, melatonergic system, mood disorders, depression, seasonal affective disorder, bipolar disorder&nbsp

Bipolar Disorder (BD) is a severe, chronic and disabling condition. The gold standard of treatment is lithium, but the introduction of Second Generation Long-Acting Antipsychotics (SGA-LAIs) has been addressed several problems in the administration of oral SGAs in BD such as the patient’s adherence to the treatment. The aim of this commentary was to provide an overview of the use of SGA-LAIs in the treatment of BD. All considered, the use of SGA-LAIs such as Risperidone Long-Acting and Aripiprazole Long-Acting may have an important impact on the maintenance treatment of BD both in monotherapy or in association with mood stabilizers. In our opinion, the treatment with a SGA-LAI should be initiated as early as possible in BD, especially when non-adherence is suspected. Moreover, as personality disorders (PD) and BD may often coexist, it is worthy to note that the PD-BD comorbidity may further decrease treatment adherence and, therefore, we believe that the early use of a SGA-LAI both in monotherapy or in association with mood stabilizers may dramatically improve the compliance and the overall outcomes in such cases. However, he safety profile should be always kept in mind when choosing an SGALAI in the treatment of BD.

Venkataramanujam Srinivasan,1 Domenico De Berardis,2,3 Timo Partonen,4 Rahimah Zakaria,5 Zahiruddin Othman6 1Sri Sathya Sai Medical Educational and Research Foundation, Coimbatore, India; 2Psychiatric Service of Diagnosis and Treatment, Giuseppe Mazzini Hospital, Teramo, 3Department of Neuroscience and Imaging, Gabriele d'Annunzio University, Chieti, Italy; 4Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; 5Department of Physiology, 6Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia Abstract: Most patients with Parkinson's disease (PD) experience sleep-related problems, such as difficulty in initiating and maintaining sleep, excessive daytime sleepiness, sleep fragmentation, reductions in non-rapid eye movement (NREM) or rapid eye movement (REM) sleep, and REM sleep behavior disorder. Although motor symptoms of PD are treated with dopaminergic drugs, the nonmotor symptoms pose a big problem, and they often precede the onset of the disease. Treating the nonmotor symptoms, such as sleep and associated behavioral disorders, is beneficial, for it not only relieves the symptoms but also helps to slow the progression of the disease. Treating PD patients with melatonin has been shown to be beneficial in treating sleep and behavior problems. The finding of reduced expression of the MT1 and MT2 melatonin receptors in amygdalae and substantia nigra of PD patients supports the involvement of melatonergic system in the etiology of PD. Hence, the use of melatonin or its analogs may even be beneficial not only for improving sleep quality but also for enhancing neuroprotection in PD. Keywords: REM sleep-behavior disorder, insomnia, melatonin receptors, circadian dysregulation

Schizophrenia is a chronic and disabling disorder, characterized by positive, negative, cognitive and affective symptoms. The first episode of schizophrenia (FES) usually occurs after a variable period of prodromic symptoms and the importance of early detection and treatment of FES has been raised in psychiatric literature from long time. In fact, it has been suggested that the first years of the schizophrenic disorder may be a critical period for long-term prognosis, as the relationship between the poor medication adherence and poorer outcome is well demonstrated. Longacting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, four SGAs-LAIs are available for the treatment of schizophrenia, risperidone long-acting injectable, olanzapine pamoate, paliperidone palmitate and aripiprazole. Several studies have also demonstrated efficacy and safety of such drugs in patients with schizophrenia. In the present paper the literature on SGAs-LAIs atypical antipsychotics in the treatment of FES will be reviewed and practical advice will be given concerning the use of this drug in the everyday clinical practice.

Domenico De Berardis1,2, Tiziano Acciavatti1, Giuseppe Di Iorio1, Mariangela Corbo1, Nicola Serroni2, Daniela Campanella2, Fabiola Di Emidio2, Monica Piersanti3, Marilde Cavuto4, Giovanni Martinotti5, Francesco Saverio Moschetta2, Massimo Di Giannantonio11Department of Neurosciences and Imaging, Chair of Psychiatry, University “G. D'Annunzio”, Chieti; 2NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”; 3NHS, Pharmaceutical Service, Hospital “G. Mazzini”, Teramo; 4IASM, L'Aquila; 5Institute of Psychiatry, Catholic University Medical School, Rome, ItalyAbstract: The circadian pacemaker or biological clock, located in the hypothalamic suprachiasmatic nucleus, is the generation site of circadian rhythms. The light/dark cycle is the circadian pacemaker's dominant synchronizing agent, though it is also influenced by neurotransmitters and the phase-shifting effects of various chemical and pharmacological components, of which melatonin (N-acetyl-5-methoxytryptamine) is the most well established. In recent years, melatonin and melatonin analogs have been commercialized in many countries, mainly with hypnotic purposes. A new compound, agomelatine, has been recently synthesized and studied. Among melatonin analogs, this drug possesses unique pharmacological and clinical features; it is an antagonist at 5-HT2B and 5-HT2C receptors and has well established antidepressant and anxiolytic properties. Agomelatine opens new perspectives in the chronobiotic treatment of depression. The purpose of the present review was to elucidate the effects of the melatonergic system on sleep and the implications for the treatment of psychiatric disorders.Keywords: melatonin, agomelatine, circadian rhythms, depression

Sleep disturbances and disruptions of circadian rhythms are underlying factors in most mood disorders like major depressive disorder (MDD) and bipolar disorder (BD), and their seasonal pattern or seasonal affective disorder (SAD). Decreases in sleep efficiency, total sleep time and sleep quality have all been documented in MDD. In addition to this, depressed patients of all these three categories (MDD, BD, SAD) exhibit profound disturbances in circadian rhythms including the sleep-wake rhythm. Circadian clock dysregulation has been suggested to be due abnormal circadian rhythmicity of gene expression. In particular, CRY1 and CRY2 polymorphisms have been shown to be associated with MDD. Similarly, variations in CRY2, PER2, ARNTL and NPAS2 are associated with SAD. An antidepressant that benefits sleep quality and resynchronize disrupted circadian rhythms will be most useful in treating mood disorders. In this context, the newly introduced melatonergic antidepressant agomelatine with MT1 and MT2 agonistic properties with 5-HT2C antagonism has been documented to be beneficial, as it improves sleep, resynchronizes the disrupted circadian rhythms, and elevates mood. This drug also manifests with fewer adverse effects and is emerging as an effective antidepressant.